Stabilitas-Obat-Mei2015

7/24/2019 Stabilitas-Obat-Mei2015

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STABILITY OF DRUGS


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The USPdefnes the stability opharmae!tial prod!t as "e#tent to$hih a prod!t retains $ithinspeifed limits% and thro!&ho!t itsperiod o stora&e and !se 'i(e itsshel lie) the same properties and

harateristis that it possessed atthe time o its man!at!rer


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Stability o dr!& also an be defned as thetime rom the date o man!at!re and

pa*a&in& o the orm!lation !ntil itshemial or predetermined le+el olabelled poteny and its physialharateristis ha+e not han&ed

appreiably( For a dr!& s!bstane, $e need to st!dy -

ate&ories o stabilities.

Solid state stability o dr!& only /ompatibility st!dies ' dr!&0 e#ipients )

Sol!tion phase stability


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Importance of stability

Extensive chemical degradation asubstantial loss of potency

Degradation products may result in adverseevents or be unsafe

Instability may cause Undesired change in performance, i.e.

dissolutionbioavailability

Substantial changes in physical appearance of the

dosage form causing product failures !e"uirement for approval by regulatory

agencies


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Fators a1etin& Stability

#$ Environmental factors. Temperat!re . Li&ht. O#y&en . 2oist!re. /arbon dio#ide

%$ Drugs or excipients in the dosage form. 3artile si4e o dr!&. p5 o the +ehile

&$ 'icrobial contamination($ )race metal *ontamination+$ eaching from containers


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Types o stability st!dies6

Physical

*hemical

'icrobiological


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3hysial stability

Physical stability implies that-. The orm!lation is totally !nhan&ed

thro!&ho!t its shel lie and has not s!1eredany han&es by $ay o appearane,

or&anolepti properties, hardness, brittleness,partile si4e et(

. It is si&nifant as it a1ets6

pharmae!tial ele&anedr!& ontent !niormity

dr!& release rate(


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ormulatioormulationn

i/ely physicali/ely physicalinstability problemsinstability problems

E0ectsE0ects

OralOral

sol!tionssol!tions7. Loss o 8a+o!r7. Loss o 8a+o!r

9. /han&e in taste9. /han&e in taste

-. 3resene o o1-. 3resene o o18a+o!rs d!e to8a+o!rs d!e to

interation $ith plastiinteration $ith plasti

bottlebottle

:. Loss o dye:. Loss o dye

;. 3reipitation;. 3reipitation


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i/ely physicali/ely physical

instability problemsinstability problems

E0ectsE0ects

3arenteral3arenteral

sol!tionssol!tions

7( Disoloration d!e to photo7( Disoloration d!e to photo

hemial reation orhemial reation or

o#idationo#idation

9( 3resene o preipitate d!e9( 3resene o preipitate d!e

to interation $ithto interation $ith

ontainer or stopperontainer or stopper

-( 3resene o "$his*ers%-( 3resene o "$his*ers%:( /lo!ds d!e to6:( /lo!ds d!e to6

'i) /hemial han&es'i) /hemial han&es

'ii) The ori&inal preparation o a'ii) The ori&inal preparation o as!persat!rated sol!tions!persat!rated sol!tion

/han&e in/han&e in

appearanappearan

e and ine and in

bio.bio.

a+ailabilitya+ailability


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ormulationormulation i/ely physicali/ely physicalinstabilityinstabilityproblemsproblems

E0ectsE0ects

S!spensionsS!spensions 7. settlin&7. settlin&

9. a*in&9. a*in&

-. rystal &ro$th-. rystal &ro$th

7.Loss o dr!&7.Loss o dr!&

ontentontent

!niormity in!niormity in

di1erent dosesdi1erent dosesrom the bottlerom the bottle

9. loss o9. loss o

ele&ane(ele&ane(


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ormulationormulation i/ely physicali/ely physicalinstability problemsinstability problems

E0ectsE0ects

=m!lsions=m!lsions 7. /reamin&7. /reamin&

9. oalesene9. oalesene

7. Loss o7. Loss o

dr!& ontentdr!& ontent

!niormity in!niormity in

di1erentdi1erentdoses romdoses rom

the bottlethe bottle

9. loss o9. loss o

ele&aneele&ane


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*oalescenc*oalescenc

ee


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ormulationormulation i/ely physicali/ely physicalinstabilityinstabilityproblemsproblems

E0ectsE0ects

SemisolidsSemisolids'Ointments'Ointments

andand

s!ppositoriess!ppositories

))

7( /han&es in67( /han&es in6

a) 3artile si4ea) 3artile si4e

b) /onsistenyb) /onsisteny

9( /a*in& or9( /a*in& or

oaleseneoalesene

-( Bleedin&-( Bleedin&

7.Loss o dr!&7.Loss o dr!&

ontentontent

!niormity!niormity

9. loss o9. loss oele&aneele&ane

-.han&e in-.han&e in

dr!& releasedr!& releaserate(rate(


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i/ely physicali/ely physicalinstability problemsinstability problems

E0ectsE0ects

)ablets)ablets /han&e in6/han&e in6

a) Disinte&ration timea) Disinte&ration time

b) Dissol!tion profleb) Dissol!tion profle

) 5ardness) 5ardnessd) Appearane 'sotd) Appearane 'sot

and !&ly orand !&ly or

beome +ery hard)beome +ery hard)

/han&e in/han&e in

dr!& releasedr!& release


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i/ely physicali/ely physicalinstabilityinstabilityproblemsproblems

E0ectsE0ects

/aps!les/aps!les /han&e in6/han&e in6

a) Appearanea) Appearaneb) Dissol!tionb) Dissol!tion

) Stren&th) Stren&th

/han&e in/han&e in

dr!&dr!&releaserelease


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/hemial stability6

*hemical stability implies- The la* o any deomposition in the hemial

moiety that is inorporated in the orm!lation asthe dr!&, preser+ati+es or any other e#ipients(

This deomposition may in8!ene the physial andhemial stability o the dr!&


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2ehanisms O De&radation

#$ 1ydrolysis-

5ydrolysis means "splittin& by $ater>>

%$ 2xidation

O#idation o inor&ani and or&aniompo!nds is e#plained by a loss oeletrons and the loss o a mole!le o

hydro&en(&$ Photolysis

It means- deomposition by li&ht


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Fators A1etin& Rates O

De&radation#$ p1 The aidity or the al*alinity o a sol!tion has a

proo!nd in8!ene on the deomposition odr!& ompo!nd(

. Aspirin b!1ered sol!tion is ma#im!m stable ata p5 o 9(:, abo+e a p5 o 7? thedeomposition rate rapidly inreases(

p5 an also in8!ene the rate o o#idation(

. The system is less readily o#idi4ed $hen the

p5 is lo$(


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Fators A1etin& Rates ODe&radation

%$ *omplexation

/omple# ormation red!es the rate o

hydrolysis and o#idation(e(&( a1eine omple#es $ith loal anesthetis,

s!h as ben4oaine, proaine and tetraaimeto a!se a red!tion in their rate o hydrolytide&radation(


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&$ Surfactants @onioni, ationi and anioni s!ratants $hen

added to sol!tions ontainin& dr!&s orm mielle

and the dr!& partiles beome trapped in themielle(

The hydrolyti &ro!ps s!h as O5 annotpenetrate this mielle o+er and reah the dr!&

partiles, hene hydrolysis rate is dereased(


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($ Presence of heavy metals 5ea+y metals, s!h as opper, iron, obalt and

ni*el inrease the rate o ormation o reeradials and enhane o#idati+e deomposition(

+$ ight and humidity

Li&ht, espeially !ltra+iolet li&ht enhanesphotolysis and h!midity enhanes hydrolytideomposition(


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Stabili4ation o dr!&s a&ainsthydrolysis, o#idation and photolysis

#$ )emperature

%$ ight

&$ 1umidity($ 2xygen

+$ *helating 3gents

4$ Solvents


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Re.test dateThe date ater $hih samples o an A3I sho!ldbe e#amined to ens!re that the material is stillin ompliane $ith the speifation and th!ss!itable or !se in the man!at!re o a &i+enF33(

Shel lie 'e#piration datin& period,onormane period)

The time period d!rin& $hih an A3I or a F33 ise#peted to remain $ithin the appro+ed shel.lie speifation, pro+ided that it is stored!nder the onditions defned on the ontainerlabel(


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Formal stability st!diesLon& term and aelerated 'and intermediate) st!dies!nderta*en on primary andor ommitment bathes

aordin& to a presribed stability protool toestablish or onfrm the re.test period o an A3I or theshel lie o a F33(

Stress testin& ored de&radation 'A3I)St!dies !nderta*en to el!idate the intrinsi stabilityo the A3I( S!h testin& is part o the de+elopmentstrate&y and is normally arried o!t !nder morese+ere onditions than those !sed or aeleratedtestin&(

Stress testin& ored de&radation 'F33)St!dies !nderta*en to assess the e1et o se+ere

onditions on the F33( S!h st!dies inl!dephotostability testin& 'see I/5 C7B) and ompatibilitytestin& on A3Is $ith eah other in FD/s and A3I's)$ith e#ipients d!rin& orm!lation de+elopment


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Stress testin& o A3I in sol!tion

Stora&e onditions Testin& period

p5 E 9, room temperat!re 9 $ee*s

p5 E , room temperat!re 9 $ee*s

p5 E 7?.79, roomtemperat!re

9 $ee*s

59

O9

, ?(7.9 at ne!tral

p5, room temperat!re

9: ho!rs

Stora&e times &i+en or ;.7; de&radation, $hate+eromes frst


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Re&!latory or ormal stability

testin&

Storage temperature(C)

Relativehumidity

(%)

Minimum timeperiod covered bydata at submission

(months)

Accelerated: 4!" #$!$

&ntermediate: '!" $!$ "

ong term: "$!" !$ " ()


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Stress testin& o F33s in solid

state

Stora&e onditions Testin& period

:?H/, ; R5 open

stora&e- months

;?.


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Importance of the rate process-

For dr!& man!at!rer as he m!stdemonstrate that his prod!t is stable andan be stored or reasonable len&th o time$itho!t han&in& to inati+e or to#i orm( The pharmaist m!st be a$are opotential instability o the dr!& that hehandles(

The physiian and the patient m!st beass!red that the presribed dr!& $ill reahthe site o ation in s!Jient onentration(


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In &eneral, reation *inetis is the st!dy orate o hemial han&e and the $ay in

$hih this rate is in8!ened by onditionso onentration o reatants, prod!ts andother hemial speies $hih may bepresent, and the ators s!h as sol+ent,press!re and temperat!re(

Reation *inetis permits orm!lation omodels or the intermediate steps thro!&h

$hih reatants are on+erted into otherhemial ompo!nds and is a po$er!l toolin el!idatin& the mehanism by $hihhemial reations proeed(


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3ccelerated stability testing

To assess the stability o a orm!lated prod!tit is !s!al to e#pose it to "hi&h stress%, i(e(ondition o temperat!re, h!midity and li&htintensity that a!se brea* do$n(

)hus these are the studies designed toincrease the rate of chemicaldegradation and physical change of a

drug by using exaggerated storageconditions as part of the formal stabilitytesting programme.


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Signi5cant change at the acceleratedconditions is de5ned as-

A ; poteny loss rom the initial assay+al!e o a bath(

Any speifed de&radants e#eedin& itsspeifed limit(

The prod!t e#eedin& its p5 limits(

Dissol!tion e#eedin& the speifed limitsor 79 aps!les or tablets(

3hysial /han&es !nder Aeleratedonditions o Temperat!re K 5!midity


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7( Under Li&ht, both 3rimary and Seondarypa*a&in& a1eted, and adin& o ontainerolor, and the print is adin&(

9( =1er+esent Tablet 6 Gain o moist!re, losso inte&rity

-( /aps!le6 /olor adin& in Blister and Sti*in&

in a Glass bottle( :( 3o$der 6 Spread $ithin strip po*ets

;( S!ppositories 6 Sotenin&


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Shelf ife Determination 6ased on3rrhenius Plot 78arret and *arper method9

The mathematial predition o shel lie is based

on the appliation o the arrhenio!s e!ation,$hih indiates the e1et o temperat!re on therate onstant, *, o a hemial reation othermodynami temperat!re, 7T, is a strai&ht

line( I the slope o this line is determined rom the

res!lts o temperat!re by e#trapolation, the *+al!e obtained( And this * +al!e is s!bstit!ted in

appropriate order o reation allo$s the amo!nto deomposition ater a &i+en time( 3reliminarye#periments are there or neessary todetermine this order(


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Reation Rate

The rate o reationis the +eloity $ith $hih a reatantor reatants !nder&o hemial

han&e(The rate,+eloity or speed o a reation is&i+en by the e#pression dc dt($here d is inrease or derease oonentration o+er a time inter+al dt


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:;3e$Ea!)

og :;og 3 $ Ea%.&here, :; rate constant !; gas

constant ;#.?@A calmole ) ;absolute temperature 3 ;fre"uency factor Ea ; energy of

activation )#


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)1E 3!!1ECIUS EU3)I2CP Q A e#p '.=aRT) '=!ation 7)* Q reation rate onstant

A Q Arrheni!s ator 'y.interept onstant)=a Q the ener&y o ati+ation or the reation, almole'7??? al Q 7 *al)R Q the ideal &as onstant, 7(N aloriesde& moleT Q the absol!te temperat!re 'de&rees Pel+in), or 9;H /TQ 9NH P and or :?H/ TQ -7-H P)

)1IS EU3)I2C *3C 6E >!I))EC IC SEE!3EUI3EC) 2!'S 3S 22>S-Ln * Q .=aRT 0 Ln A '=!ation 9, y Q m# 0 b)Ln *9*7 Q .=aR'7T9.7T7) '=!ation -)*9 Q *7 e#p.=aR'7T9.7T7) '=!ation :)

The onstants *7 and *9 are the rate onstants at temperat!reT7 and T9 'or e#ample 9; de&rees / and :?de&rees /), respeti+ely


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The lo& time to ? is then plotted a&ainst 7T andthe time or 7? loss o poteny at room temp( anbe obtain rom the res!ltin& strai&ht line bye#trapolation to 9;?/


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